Process for the conversion of the angular methyl groups of steroids



United States Patent 3,385,848 PRUQESS FGR THE CONVERSTQN 6F THE ANGULAR METHYL GRGUPS 0F STERGZDS Albert Wettstein, liliehen, Gskar .ieger, Zurich, Georg Anner, Karl Heusler, and .larosiav Kaivoda, Basel, Charles Meystre, Reinach, and Feter Wieland, Basel, Switzerland, assignors to Ciha Qorporation, New York, N.Y., a corporation of Deiaware No Drawing. Continuation-impart of application Scr. No. 1il2,114, Apr. 11, 1961. This application Sept. 19, 1962, Ser. No. 224,347 Claims priority, appiication Switzerland, Apr. 14, 196i), 4,272/50; Sept. 22, 1951, tidied/d1 29 Claims. (62. 26il-239.55)

ABSTRACT 9F THE DISCLQEURE The invention includes oxygenation of the angular methyl groups in positions 10 and 13 of steroids by treat ing llfs-hydroxysteroids with heavy metal acylates having an oxidizing action in the presence of iodine, and if desired treating the resulting iodides with a hydrolysing or acylolytic agent and/or oxidising the products so obtained. The process furnishes 18:1l,8-oxidosteroids or 19:11fl-oxidosteroids which may be substituted in position 18 or 19 by iodine or by alkoxy or acyloxy groups. The lit-substituted or 19-substituted 115:18-oxido or 11s: 19-oxido compounds are transformed either by direct hydrolysis or by exchange of the iodine atom for anacyloxy radical and subsequent acid or alkaline hydrolysis into 18-hydroxy-18:llfi-oxidosteroids or 19-hydroxy- 19:11fl-oxidosteroids representing the hemiacetals of the 1l,B-hydroxy S-als or -l9-als respectively. These compounds, or also the iodo compounds, can if desired, be oxidised to the l8zllfi-lact0nes or 19: llfl-lactones of the steroid-IS-acids or -l9-acids which are also formed by direct oxidation of the resulting unsubstituted oxidosteroids with, for example, chromium trioxide or ruthenium tetroxide.

This is a continuation-in-part of application Ser. No. 102,114, filed Apr. 11, 1961, and now abandoned.

The present invention provides a process for the oxidative conversion of the angular methyl groups of steroids.

The invention is based on the observation that the angular methyl groups in positions 10 and 13 can be oxygenated in a simple manner by treating llfi-hydroxysteroids with heavy metal acylates having an oxidising action in the presence of iodine, and if desired treating the resulting iodides with a hydrolysing or acylolytic agent and/or oxidising the products so obtained.

The present process furnishes 18:1lfl-oxidosteroids or 19:11/3-oxid0steroids which may be substituted in position 18 or 19 by iodine or by alkoxy or acyloxy groups. The IS-substituted or 19-substituted 11,8118-oxido or 11:19B-oxido compounds are transformed either by direct hydrolysis or by exchange of the iodine atom for an acyloxy radical and subsequent acid or alkaline hydrolysis into 18-hydroxy-l8:llfl-oxidosteroids or 19-hydroxy- 19:11l3-oxidosteroids representing the hemiacetals of the llfl-hydroxy-lS-als or -19-als respectively. These compounds, or also the iodo compounds, can if desired, be oxidised to the 18:11i3-laetones or 19:11f3-lactones of the steroid-lB-acids or -19-acids which are also formed by direct oxidation of the resulting unsubstituted oxidosteroids with, for example, chromium trioxide or ruthenium tetroxide.

'ice

The reactions of the invention may, for example, be represented by the following scheme of partial formulae:

Ho cs X=OH, Oacyl, I, H,

-0R R= ether radical The resulting 18-oxygenated compounds, more especially those of the pregnane series, are important intermediates for the preparation of compounds of the type of the highly active adrenocortical hormone aldosterone. The 19-oxygenated compounds, on the other hand are very important for the preparation of 19-oxygenated steroids of the type of Strophantin and its conversion products, more especially for the manufacture of the important 19- norsteroids.

Where the main product formed is an 18-oxid0 or a 19- oxido compound seems to depend substantially on the configuration of the rings A and B and on the substitution of the steroid skeleton. While compounds containing a double bond in position 4:5 or 5:6 yield predominantly 11:19-oxidosteroids, the compounds of the 5aand 55- series that are saturated in said positions yield a mixture of 18:11- and 19:1l-oxido-steroids.

According to the present process the llfl-hydroxy steroids used as starting materials are reacted with compounds yielding oxidising acyloxy radicals, such as oxydising heavy metal acylates, preferably lead tetraacetate, in the presence of iodine, if desired, with addition of a weak base, and/or with irradiation. The process can be performed, for example, as follows: The starting material is dissolved in a solvent that is inert towards the oxidant, for example in a hydrocarbon; lead tctraacetate, iodine and a weak base, for example calcium carbonate, are then added, and the reaction mixture is stirred and heated under atmospheric or superatmospheric pressure. Particularly suitable solvents are saturated cyclic hydrocarbons, such as cyclohexane, methyl-cyclohexane, dimethylcyclohexane, aromatic hydrocarbons, such as benzene, or mixtures of said solvents. The requisite time of reaction depends on the temperature and/ or the solvent used. When the reaction is performed in boiling cyclohexane, the reaction is as a rule complete after about 6 hours. According to an advantageous variant of the process lead tetraacetate is first reacted with iodine in the presence of calcium carbonate, and the ll-hydroxysteroid is then added. It is of advantage to initiate and accelerate the reaction by irradiation with natural or artificial light. For working up the reaction mixture the inorganic salts are filtered off and any excess of iodine present is removed by agitation with thiosulfate solution.

The reaction products present in the reaction solution are in part 11fi,18-oxidoand 11,8,19-oxido steroids and in part 18-hydroxy-11,18-oxido or 19-hydroxy-11,19- oxido-steroids, especially in the acetylated form. The 18- iodo-l1 3:18-oxido or 19-iodo-1l/3:19-oxido steroids may be hydrolysed, for example by treatment With sodium acetate and dilute acetic acid, whereby at the same time-if this has not already occurred during the treatment with lead tetraacetate and idineany existing ketals and acetals are split to form free ketones and alde hydes, or hemiketals or hemiacetals respectively. In particular, 18-iodo-11B: 18-oxido-20-ethylenedioxypregnanes give rise to 11/9-hydroxy-18:ZO-dioxopregnanes which may also be present as 1113:18-oxido-18-hydroxy compounds. When, on the other hand, the crude reaction product is reacted in a neutral solvent (for example in acetone or dimethyl formamide) with an alkali metal salt or heavy-metal salt of a carboxylic acid (for example with sodium acetate, potassium acetate or silver acetate), the 18-iodo or 19-iodo compounds yield the 18-acyloxy or 19-acyloxy compounds respectively, from which the free l8-hydroxy or 19-hydroxy compounds are obtained by acid hydrolysis, for example by heating with dilute acetic acid or with an aqueous mineral acid in a watermiscible solvent, or by alkaline hydrolysis, for example with an alkali metal bicarbonate, carbonate or hydroxide.

For the conversion of the 18-hydroxy-18z1lB-oxido and 19-hydroxy-19z11fl-oxido compounds of the invention into the 18:1lB-lactones and 19:11/3-lactones respectively, a variety of oxidants is available, above all compounds of hexavalent chromium, such as chromium trioxide, for example in the form of the pyridine complex, or in acetic acid or sulfuric acid solution, or manganese dioxide. The 18:11B-lactones and 19:11fl-lactones can also be made directly from the crude products containing the 18-iodo-18:11,B-oxido or 19-iodo-19:11;8-oxido compounds, when the oxidation is conducted in the presence of a heavy-metal chromate, for example lead chromate or more especially silver chromate. A small amount of lactones is even formed already during the treatment of the IIB-hydroxy steroids with iodine and the heavy metal acylate under the action of such oxidative mixture.

Starting materials suitable for use in the present process are llp-hydroxy compounds of the androstane, pregnane, cholane, cholestane, stigmastane, spirostane and cardanolide series whose ring system may contain further substituents, more especially in one or several of the positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 14, 15, 16, 17, 21, such as free or functionally converted 0x0 groups, or esterified or etherified hydroxyl groups, alkyl, for example methyl, groups and/or halogen atoms. The term functionally converted oxo groups describes ketalized oxo groups or oxo groups converted into enol derivatives, such as enolethers and enolesters. Furthermore, the starting materials may also contain double bonds or oxido groups, for example, starting from carbon atom or in position 16:17. Specific starting materials are, for example, the following compounds: 3a-acyloxy-1 1 B-hydroxy-17-ethylenedioxy-5B-androstanes, 318: 17fi-diacyloxy-1 lfl-hydroxy-5a-androstanes,

A -3 -ethylenedioxy-l 1 ,B-hydroxy-17,8-acyloxyandrostenes,

A -3 :20-bisethylenedioxy-l lfi-hydroxypregnene,

A -3 :20-dioxo-1 lfi-hydroxy-Z l-acyloxypregnenes,

3 a-acyloxy-l 1 fi-hydroxy-ZO-ethylenedioxy-S fi-pregnanes,

3/8-acyloxy-1 1 ft-hydroxy-20-ethylenedioxy-Sa-pregnaneS,

3 :20-bisethylenedioxy-1 lfi-hydroxy-Z1=acyloxy-5flpregnanes,

3a-acyloxy-1IB-hydroxycholanic acid methyl ester,

A -3p-acyloxy-1 lfi-hydroxycholestenes,

3 fl-acyloxy-l lfi-hydroxyspirostanes, A -35-acyloxy-1lfi-hydroxyspirostenes, A -3-ethylenedioxy-1lp-hydroxyspirostenes, and the like.

Another object of the invention are l9-iodo-ll}8:l9- oxidosteroids, 19-hydroxy-11B:19-oxidosteroids, 1l/8-hydroxy-19-oxosteroids and 11}3:l9-lactones of llfi-hydroxysteroid-l9-acids, more especially such steroids as contain a double bond in position 4:5 or 5:6. The aforementioned l9-substituted steroids may belong to the androstane, pregnane, cholanic acid, spirostane, cardanolide or cholestane series. As specific compounds there may be mentioned the following compounds: A -3:20- dioxo 19-iodo-l1,8:19-oxidopregnene, A -3z20-dioxo-l9- hydroxy-llfi:19-oxidopregnene, and the 19:11-lactone of A -3:20-dioxo-1lfi-hydroxypregnene-l9-acid as well as the corresponding A -3:20-bisethyleneketals; also the 19:11- lactone of 3 oc-acetoxy-l1fl-hydroxy-ZO-oxo-S/i-pregnane-19-acid, A -3-oxo-17fi-hydroxy-19-iodo-11B:19-oxidoandrostene,

-3-oxo-17;8:19-dihydroxy-11fi: 19-oxidoandrostene,

and the 19: ll-lactone of A -3-oxo-11B:17,6-dihydroxyandrostene- 19-acid and their l7-esters and A -3-ethyleneketals.

The above-mentioned compounds are valuable intermediates for the manufacture of 19-nor steroids which can be obtained as follows:

When, after having introduced the 19-oxo or 19-acid grouping, a A -3-oxo grouping is formed, by oxidising a A -3-hydroxy grouping, or by ketal cleavage of a A -3- ethyleneketal, the angular aldehyde or acid group is easy to eliminate by treatment with an alkaline agent, for example by heating with an alkali metal hydroxide, in an anhydrous or aqueous solution, with formation of a 19- nor steroid. Thus, the A -3-oxo-l1,8:l9-oxido-l7:l9-dihydroxyandrostene which is easy to prepare by the present process, or the 19:11-lactone of A -3-oxo-llfi:l7fi-dihydroxyandrostene-9-acid respectively, yields on treatment with an alkali A -3-oxo-11fi:17,8-dihydroxy-19-nor androstene in which, if desired, the llfl-hydroxy group can be eliminated in known manner, to yield the known 19- nortestosterone. The 19:1l-lactone of A -3z20-dioxo-llflhydroxypregnene-9-acid yields in a similar manner 11,8- hydroxy-l9-norprogesterone, or after elimination of water and isomerisation of the double bond formed, the progestatively active 3:20 dioxo A4300) 19 norpregnadiene. llB-hydroxydiosgenin yields, via A -3fi-acetoxy- 11,6:19-oxido-19-hydroxyspirostene, and by subsequent oxidation according to Oppenauer and alkali treatment, the A -3-oxo-1lfi-hydroxy-19-norspirostene which is degraded in a manner similar to that for the corresponding IO-methyl compound to 1Iii-hydroxy-19-norprogesterone.

The invention further includes 18-iodo-11,B:18-oxido- Steroids and 18-hydroxyand 18-alkoxy-1lfiz18-oxidosteroids saturated in rings A and B viz. 1l/3-hydroxy-18- oxosteroids, and 18:1l-lactones saturated in rings A and B of 1lfi-hydroxysteroid-l8-acids, more especially of the Suregnane and Sfi-pregnane series. The Sea-pregnanes may contain a hydroxyl group in position 35, and the 519- compounds in position 30:. As specific compounds the following may be mentioned: 3a-hydroxy-11 3:18-oxido-18- iodo-ZO-oxo-Sfl-pregnane, 3oc-l8-dihYdI'OXY-1 113: 18-oxido- ZO-oxo-SB-pregnane and its 18-ethylene glycol ether, the 18:1l-lactone of 3a:11B-dihydroxy-20-oxo-5B-pregnane- 18-acid and the corresponding 3-esters and/or ZO-ethyleneketals, 3:20 dioxo 11,8:18-0xido-18-iodo-21-hydroxy 5aand Sflregnane, 3:20-dioxo-ll;8:l8-oxido- 18:21-dihydroxy-5uand -5fl-pregnane, the 18:11-lactone of 3.20 dioxo llfl:2l-dihydroxy-5aand -5fl-pregnane- IS-acid, and their esters and/or 3:20-biethyleneketals or 3-monoethyleneketals.

The present invention further includes l9-unsubstituted 115:19-oxidosteroids which are saturated in the rings A and B of the skeleton or contain double bonds, for example in positions 45 or 5-6, more especially steroids of the androstane and pregnane series. As specific compounds there may be mentioned: 3ot-hydroxy-20-oxollflzl9-oxido-5e-pregnane and the corresponding esters, 3:20-dioxo-11B: 19-oxido-A -pregnene and ZO-ketals or 3- ketals, or 3:20 diketals thereof. These new 115:19-oxidosteroids are likewise important intermediates for the manufacture of 19-nor-steroids, e.g. 3:20-dioxo-A -19- norpregnadiene. Thus, the first-named compound can be converted by oxidation with, for example, chromiumtrioxide+pyridine complex, subsequent bromination and dehydrobromin-ation, into 3:20 dioxo-llfizl9-oxido-a pregnene which, on treatment with acetic anhydride and para-toluenesulfonic acid and subsequent hydrolysis, is transformed into 3:20 dioxo-19-hydroxy-A -pregnadiene which can be converted into the above-mentioned product by basic treatment, for example the methanolic sodium hydroxide solution.

The 11,18-oxido-pregnane compounds obtainable by the present process are valuable intermediates for the manufacture of aldosterone and kindred compounds. Thus, for example, the 18:11-lactone of 3oc-EICC'tOXY-11B- hydroxy-20-oxo-Sfl-pregnane-18-acid is easy to hydrolyse with aqueous'methanolic hydrochloric acid to form the corresponding 3-hydroxy compound which, on oxidation with chromium trioxide in glacial acetic acid, yields the 18: ll-lactone of 3 :20-dioxo-11,8-hydroxy-5/3-pregnane-18- acid which, on bromination and dehydrobromination, is converted into the known 18:11-lactone of A -3:20dioxo- 1lfi-hydroxypregnene-l8-acid. In a similar manner the 18:11-lactone of 3:ZO-dioxo-llfi-hydroxy-Zl-acetoxy-SB- pregnane-l8-acid yields on bromination and dehydrobromination the corresponding, known A -3-ketone which, on treatment with ethylene glycol and para-toluene-sulfonic acid in known manner, yields the 18:11-lactone of A 3 -thylenedioxy 11,8 hydroxy-20-oxo-2l-acetoxypregnene-l8-acid, which is also a known intermediate of the synthesis of aldosterone. The 3:20-dioxo-1l,8:18- oxido-18:2l-dihydroxy-Sfl-pregnane, on the other hand, can be converted directly into an aldosterone-18z21-diacylate, after esterification of the two free hydroxyl groups by bromination and dehydrobromination.

In similar, known manner the corresponding Six-pregnanes can be converted into the A -3-keto derivatives. Of special value is the 3:20-dioxo-1lfl:18-oxido-18z21-dihydroxy-Sa-pregnane (4:5-dihydroaldosterone) and its 21- esters, for example the formate, acetate, propionate, benzoate, trimethylacetate, phenylpropionate, meta-sulfobenzoate, phosphate, sulfate or the like, as well as the 18:11-lactone of 3:20 dioxo-lltiz2l-dihydroxy-5a-pregnane-18-acid and its 21-esters. These compounds, more especially the first-named, in the form of water-soluble derivatives, possess a narcotic-sedative action and it can also be used for normalizing the circulation of blood in shock conditions such, for example, as are caused by certain endotoxins.

In the esters of the products obtained by the present process the acid radicals are those of saturated or unsaturated aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic acids, preferably such having from 1 to 20 carbon atoms, for example those of formic, acetic, propionic, a butyric or valeric acid such as n-valeric or trimethylacetic acid, a caproic acid such as B-trimethylpropionic acid, of oenanthic, caprylic, perlargonic, capric acid, an undecylic acid, for example undecylenic acid, of lauric, myristic, palmitic or stearic acid, for example oileic acid, of a cyclopentyl-cyclohexylor phenyl-acetic or propionic acid, benzoic acid, a phenoxy-alkane acid such as phenoxyacetic, para-chlorophenoxyacetic, 2:4-dichlorophenoxyacetic, 4-tertiary butylphenoxyacetic, 3- phenoxypropionic acid, 4-phenoxybutyric acid, of furan- 2-carboxylic acid, S-tertiary butyl-furan-Z-carboxylic acid, 5-brorno-furan-2-carboxylic acid, a nicotinic or dicarboxylie acid such as oxalic, succinic or glutaric acid, of

substituted carboxylic acids such as B-ketocarboxylic acids, for example of acetoacetic, propionylacetic, butyrylacetic or caprinoylacetic acid, of amino acids and the like.

The following examples illustrate the invention.

EXAMPLE 1 A mixture of 12.0 grams of dried lead tetraacetate, 4.0 grams of calcium carbonate and 400 cc. of cyclohexane is heated for a short time at C., then mixed with 3.2 grams of iodine and refluxed for one hour with the aid of an infrared heater. The violet solution is allowed to cool slightly and mixed with 2.00 grams of 3a-acetoxyhydroxy 20 ethylenedioxy-5,8-pregnane, and the whole is stirred on under reflux for 3 hours and then cooled to 20 C., the reaction mixture is filtered and the filter cake rinsed with 500 cc. of absolute ether. The filtrate is washed in a separating funnel once with 40 cc. of a sodium thiosulfate solution of 25% strength and 3 times with water, and then evaporated under vacuum at 20 to 25 C.

A solution of the evaporation residue (which contains inter alia 3aacetoxy-l1fl:18-oxido 18 iodo-20-oxo-5B- pregnane) in 20 cc. of pyridine is added to a stirred suspension, cooled to 5 C., of 2.0 grams of chromium trioxide and 4.0 grams of silver chromate in 20 cc. of water and 20 cc. of pyridine; the reaction mixture is stirred for 16 hours at 60 C., then diluted with ether and water, undissolved constituents are filtered oif, the aqueous layer is separated, the ethereal solution washed 3 times with water, dried with sodium sulfate and evaporated under vacuum. The resulting amorphous product (2.20 grams) is dissolved in 20 cc. of benzene and chro matographed on anhydrous silica gel. Elution with benzene+ethyl acetate 4:1 furnishes, successively: 742 mg. of an oil which on prolonged trituration with ether yields 128 mg. of the 18:11-lactone (melting at 160165 C.) of 30a acetoxy-llfl-hydroxy-ZO-oxo-Sfl-pregnane-18-acid; then 590 mg. of an oil from which there are obtained mg. of a further crystalline compound (melting at 146- 149 C.) which on another crystallization from ether-l-petroleum ether yields 3a-acetoxy-20-oxo-11:19-oxido-5t3- androstane melting at 165169 0.; optical rotation [a] =+72.3i1 (c=0.763). The infrared spectrum of the compound contains absorption bands inter alia at 5.76, 5.86, 7.32, 8.09, 9.59, 9.80 and 9.85s. Furthermore, there were eluted 450 mg. of a crystalline crude fraction which, on recrystallization from methylene chloride-i-ether, yields 275 mg. of the 18-glycol ether of 3aacetoxy-l8-hydroxy -11/3z18 oxido-20-oxo-5/i-pregnane melting at 202-204" C. Optical rotation [a] =+147.7 (c=0.998). The infrared spectrum contains absorption bands inter alia at 2.85, 5.80, 5.90, 8.10, 8.95, 9.12, 9.45, 9.70, 9.95, 10.15 and 1050 (in methylene chloride).

A lzl-mixture of benzene and ethyl acetate elutes small amount (80 to 100 mg.) of 3ot-21C6iOXY 'l8-hYdIOXY- ZO-oxo-llfi: l8-oxido-5B-pregnane melting at 205-208 C. (in admixture with the glycol ether described the mixed melting point is by 10 C. lower). Optical rotation [a] +99 (c.=0.987). Absorption bands in the infra red spectrum occur at 2.78, 2.92, 5.77, 5.85, 7.25, 7.34, 8.10, 9.55, 9.72 and 11.00/L. The same compound can also be obtained by subjecting the glycol ether described to acid hydrolysis.

hThe compound used as starting material is prepared t us:

8.73 grams of 3or-acetoxy-11-oxo-20-ethylenedioxy- SB-pregnane (prepared by partial ketalization of 3aacetoxy-ll:ZO-dioxo-S/B-pregnane), dissolved in cc. of absolute tetr-ahydrofuran, are added dropwise to a cooled, vigorously stirred suspension of 8.5 grams of lithium aluminum hydride in 350 cc. of absolute tetrahydrofuran, and the reaction mixture is refluxed for 2 hours. The excess reducing agent is decomposed by adding 17 cc. of ethyl acetate; 20 cc. of saturated sodium sulfate solution and 60 grams of solid anhydrous sodium sulfate are added, the whole is filtered, the residue is rinsed exhaustively with tetrahydrofuran, benzene and methylene chloride, and the filtrate is evaporated, to yield 8.30 grams of crude 3azllfi-dihydroxy -20 ethylenedioxy-SB-pregnane which, after one recrystallization from ethyl acetate+petroleum ether, melts at 141.5- 143 C. Yield: 7.40 grams.

A solution of 7.30 grams of 3azll/fi-dihydroxy-20- ethylenedioxy-Sfi-pregnane in 40 cc. of pyridine and 40 cc. of acetic anhydride is kept for 12 hours at 20 C. The solution is then concentrated under vacuum, mixed with Water and extracted with ether+methylene chloride 4:1. The extract is washed with Water until the Washings run neutral, dried and evaporated to yield a crystalline residue from which by direct crystallization from methylene chloroide-i-methanol there are obtained 6.61 grams of 3a-acetoxy-1l,B-hydroxy-Z0-ethylenedioxy-5/3- pregnane in the form of small prisms melting at 163 C. The infrared spectrum of the compound contains absorption bands at 2.36, 5.80, 8.07, 9.30, 9.47, 9.72, 10.15 and 10.5

EXAMPLE 2 A solution of 100 mg. of 3u-acetoxy-18-hydroxy- 11:18-oxido-20- xo-SB-pregnane in 2.5 cc. of glacial acetic acid is mixed with 12 cc. of a solution of 1% strength of chromium trioxide in glacial acetic acid of 95% strength, and the whole is kept for 2 /2 hours at 20 C. The excess of the exidising agent is decomposed with 10 cc. of methanol, the reaction solution is evaporated under vacuum, and the residue is taken up in ether+ methylene chloride. The solution is Washed 3 times With water, dried and evaporated. One recrystallization of the product isolated in this manner from methylene chloride+petroleum ether yields 65 mg. of the pure 18:11- lactone of 3a-acetoxy-11/3-hydroxy-20-oxo-5fl-pregnane- 18 acid melting at 195-198 C. Optical rotation [a] =+7O (c.:0.86). I-ts infrared spectrum contains bands inter alia at 5.68, 5.77, 5.85, 8.10, 8.57, 9.05, 9.27, 9.72,10.16, 10.72, 11.30 and 12.15 4.

30 mg. of the 18:1l-lactone of 3a acetoxy -11B -hydroxy-20-oxo-5,8-pregnane-18-acid are dissolved in cc. of methanol, 0.5 cc. of concentrated hydrochloric acid is added, and the whole is kept for 60 hours at 20 C. The clear reaction solution is concentrated under vacuum to about 1 cc., taken up in ether, washed four times with water, dried, and evaporated under vacuum, to yield 24 mg. of a colorless foam which crystallizes on being sprinkled with ether. After one recrystallization from a mixture of methylene chloride, ether and petroleum ether, the resulting 18:11-lactone of 3a:1l[3-dihydroxy 20 oxo 5 3-pregr1ane-18-acid melts at 190- 191 0; its infra-red spectrum contains absorption bands inter alia at 2.78, 5.65, 5.86, 8.60, 9.06, 9.65, 10.12, 10.65 and 10.75

A solution of 14.5 mg. of the 18: ll-lactone of 3a:11,8- dihydroxy-ZO-oxo-Sfl-pregnane-18-acid in 1 cc. of glacial acetic acid is mixed with a solution of 24 :mg. of chromium trioxide in 1 cc. of glacial acetic acid and 0.1 cc. if water, and the mixture is kept for 2 /2 hours at 20 C. The excess chromic acid is decomposed with 3 cc. of methanol, the reaction solution is evaporated under vacuum, and the residue is taken up in ether and washed with water until neutral. Evaporation of the dried ethereal solution furnishes 11.5 mg. of an amorphous product which is chromatographed on silica gel to yield 6.8 mg. of a crystallizing product which, according to its infrared spectrum, is the slightly impure 18:11-lactone of 3:20-dioxo-1I/S-hydrOxy-S S-pregnane-lS-acid. After recrystallization from methylene chloride-l-hexane the fine needles melt at 228-23 C. The infrared spectrum contains bands inter alia at 5.63, 5.84, 6.92, 7.33, 8.25, 8.50, 8.70, 8.85, 9.05, 9.85, 10.12, 10.49 and 10.70 1.

The paper-chromatogram of the compound in the systerns formamide/benzene and formamide/cyclohexanebenzene 1:1 reveals the same Rf values (0.75 and 0.3 respectively) as a preparation obtained by hydrogenation of the 18:11-lactone of d:l-A -3:20-dioxo-11,8-hydroxypregnene-18-acid.

EXAMPLE 3 1.6 grams of iodine are added to a suspension, boiled for a short time, of 2.0 grams of calcium carbonate and 6.0 grams of pre-dried lead tetraacetate in 250 cc. of cyclohexane, and the mixture is refluxed for 1 hour. Thereupon 1.0 gram of A -3z 20 bisethylenedioxyal1p?- hydroxy-pregnene is added. The Whole is refluxed While being stirred for another 4 hours, by which time the reaction solution has become colorless; it is cooled to 20 C., filtered through a glass suction filter, and the residue is exhaustively washed with absolute ether. While cooling the filtrate with ice, it is agitated once with 20 cc. of a solution of sodium thiosulfate of 25% strength and three times with water, mixed with 3.0 grams of sodium acetate and 3.0 cc. of glacial acetic acid, and evaporated under vacuum. The residue contains, inter alia, A -3 :20-bis-ethylenedioxy 11,6119 oxido 19 iodopregnene; it is taken up in 30 cc. of acetic acid of strength, heated for 2 hours at C., and the reddish solutions mixed with cc. of water and evaporated under vacuum. The residue contains A -3:20-dioxo- 11,3:19-oxido-19-hydroxy-pregnene; it is extracted with ether+methylene chloride 4:1, and the resulting solution is washed With Water, sodium bicarbonate solution and water, dried and evaporated. There are obtained 1.15 grams of a yellow foam which is taken up in 6 cc. of pyridine, mixed at 0 C. with a solution of 1.50 grams of chromium trioxide in 3.0 cc. of water and 3.0 cc. of pyridine, and the whole is oxidised for 18 hours. '15 grams of ice and 10 cc. of a sodium hydrosulfite solution of 40% strength are then added to the reaction mixture. After 15 minutes, the green solution is acidified with 2N- hydrochloric acid to acid reaction to Congo red and then extracted with ether+methylene chloride. The solution is washed neutral, dried and evaporated, to yield 1.05 grams of a yellowish foam.

A solution of 380 mg. of the crude product in benzene is chromatographed on silica gel. Apart from several unidentified products a crystalline fraction (45 mg.) is obtained which, after recrystallization from methylene chloride+petroleum ether, yields the 19:11-lactone of A -3 :20-dioxo 11fi-hydroxypregnene 19 acid melting at =206-208 C. Subsequent preparative paper-chromatography furnishes a completely pure product; its infrared spectrum in carbon disulfide contains absorption bands inter alia at 5.60, 5.67, 5.76, 5.93, 7.31, 7.90, 8.17, 8.67, 9.05, 9.38, 9.64 and 10.06 1.

Alternatively, the product obtained by reacting 3z20 diethylenedioxy-rllfi-hydroxy-A -pregnene with lead tetraacetate and iodine can be Worked up in the following manner:

The reaction mixture is filtered through Celit, rinsed with cyclohexane, a few drops of pyridine are added, and the whole is evaporated under vacuum. The residue is taken up in 45 cc. of pyridine, an identical amount of silver acetate is added, and the whole is heated with stirring for 3 hours at 50 C. Inorganic constituents are then filtered off and the filtrate is evaporated under vacuum. By subsequent chromatography on silica gel there is obtained, inter alia, 3-ethylenedioxy-llfi-l9-oxido- 20-oxo-A -pregnene melting at 179-182 C. in a yield of about 15%. Optical rotation [u] =+108.8 (0:0.912). The infrared spectrum of the compound contains bands inter alia at 5.86, 6.75, 7.35, 9.15, 9:56, 9.70, 10.13 and 1055 1. and 11.82,. By treatment with dilute acetic acid (2:1) for 20 minutes at 100 C., crystalline 3 :20-dioxo 1.15: 19 oxido A pregnene is obtained; its infrared spectrum contains absorption bands at 5.89, 6:02, 6.22, 7.40, 8.25, 9.68, 9.77, 10.02 and 115211. The

chromatogram further yields a small amount (about of S-ethylenedioxy-Ll-hydroxy-20-oxo-A -pregnene melting at 225 C., whose infrared spectrum contains bands at 5.86, 7.40, 8:88, 9:10, 9.40, 9.60, 9.75, 10:16 and tl'1.75,u..

The A 3 :20 bisethylenedioxy 11 B-hydroxypregnene used as starting material for the reaction described in Example 3, is prepared in the following manner:

A solution of 2.95 grams of A 3:ZO-bisethylenedioxyll-oxopregnene in 50 cc. of absolute tet-rahydrofuran is added dropwise within 15 minutes to a stirred and icecooled suspension of 1.8 grams of lithium aluminum hydride in 480 cc. of freshly distilled absolute tetrahydrofuran. The cooling bath is then replaced by a heating jacket, and the reaction mixture is stirred and refluxed for 2 hours. The excess reducing agent is then decomposed by adding 10 cc. of ethyl acetate to the ice-cooled mixture, and the aluminum hydroxide is precipitated in a filterable form with 10 cc. of saturated sodium sulfate solution and ;15 grams of solid sodium sulfate. The precipitate is then suctioned off, exhaustively washed with tetrahydrofuran, benzene and methylene chloride, and the combined filtrates are evaporated under vacuum. The oily residue crystallizes when it is sprinkled with ether. After two recrysallizations from methylene chloride +petroleum ether, there are obtained 2.432 grams of A -3:ZO-bis-ethylenedioxy-llfi-hydroxypregnene in the form of fine needles melting at 147-148 C. (Another modification of the identical product melts at 138 (3.). Optical rotation [u] =22.1 (c= 1.22 in chloroform).

EXAMPLE 4 800 mg. of iodine are added to a suspension, heated for a short time at 80 C., of 1.0 gram of calcium carbonate and 3.0 grams of pre-dried lead tetraacetate in 200 cc. of cyclohexane, the mixture is heated with stirring for 1 hour at 80 C. and then cooled to about 60 C.; 445 mg. of corticosterone acetate (A -3z20 dioxo 11,8-hydroxy-2'1-acetoxy-pregnene) are then added, and the deep violet reaction solution is refluxed and stirred for 4 hours. The mixture has by then become colorless; it is freed by filtration from solid constituents, the residue is thoroughly washed with 150 cc. of absolute ether, the filtrates are combined, washed with a solution of 5.0 grams of sodium thiosulfate in 10 cc. of water, then agitated with 2X50 cc. of water and evaporated under vacuum in a flask containing 1.5 grams of sodium acetate and 1.5 cc. of dimethyl formamide. 15 cc. of dimethyl formamide are added to the residue which is then heated for 2 hours at 100 C.; the brown reaction mixture is evaporated in a high vacuum, the resulting residue is taken up in ether+ methylene chloride 4:1, and the solution is washed neutral with water, dried and evaporated, to yield 416 mg. of crude A -3:20-dioxo-11,8: l9 oxido-19:ZI-diacetoXy-pregnene in the form of a brown oil which is dissolved in 15 cc. of acetic acid of 70% strength and kept for 10 hours at 20 C. The solvent is then evaporated under a high vacuum at 20 C. and the residue is worked up with ether-l-methylene chloride and water. The yield of crude reaction product amounts to 400 mg; it is decolorized by filtration through silica gel, and 225 mg. of the purified productwhich still consists of a mixture of over 3 substances-is subjected to preparative separation on 150 sheets of paper in the system formamide/cyclohexanebenzene 1:2. One of the two less polar zones yields on extraction 102 mg. of crystals contaminated with oil. After two recrystallizations from ether+petroleum ether there are obtained 20 mg. of the 19:11-lactone of A -3z20-dioxo-llfi-hydroxy-Zl acetoxypregnene-19-acid melting at 120-122 C.

The infrared spectrum contains absorption bands inter alia at 5.60, 5.68, 5.75, 5.93, 7.82, 7.90, 8.17, 8.67, 9.38, 9.65 and 10.05

EXAMPLE 5 A suspension of 6.0 grams of lead tetraacetate and 2.0

grams of calcium carbonate in 200 cc. of cyclohexane is heated with stirring at the boil for 30 minutes. 1.0 gram of 3:20-bisethylenedioxy 11B hydroxy-2l-acetoxy-5apregnane and 1.6 grams of iodine are then added, and the whole is boiled with stirring, and while being irradiated with a 200 watt lamp, until the iodine color has disappeared (about 1 to 1 /2 hours). The reaction mixture is then cooled and filtered, and the filter residue is rinsed with 150 cc. of ether. The filtrate is then washed with 100 cc. of sodium thiosulfate solution of 10% strength and with water. 3.0 grams of dry sodium acetate and 10 cc. of dimethyl formamide are then added to the dried organic solution, and the mixture is evaporated under a water-jet vacuum at a bath temperature of 30-35 C. The residual oil is diluted with a further 10 cc. of dimethyl formamide and heated for 2 hours at C. The solvent is then distilled off substantially completely under 0.1 mm. Hg pressure, the residue is dissolved in methylene chloride, and the solution is repeatedly Washed with water. The dried methylene chloride solution is evaporated and the residue (1.27 grams), which contains the 3:20-bisethylenedioxy-llfl:18-oxido 18:21 diacetoxy-5m-pregnane, is dissolved in 30 cc. of aqueous acetic acid of strength and boiled for 20 minutes under nitrogen at a bath temperature of 140 C. The reaction mixture is alloWed to cool, evaporated under a water-jet vacuum, and the residue is dried by being repeatedly evaporated with xylene and benzene under a water-jet vacuum, to yield 800 mg. of a yellow oil. 200 mg. of this crude product are subjected to preparative paper-chromatography on 120 sheets of Whatman paper in the system formamide-benzene. The zone of R =0.5, which gives a positive reaction with blue tetrazolium, is cut out, successively pasted with 500 cc. each of 20% aqueous tetrahydrofuran, 50% aqueous tetrahydrofuran and undiluted tetrahydrofuran, and after each pasting again suction-filtered. The filtrates are freed under a water-jet vacuum from tetrahydrofuran, the aqueous solution is extracted with methylene chloride, and the extracts are dried and evaporated. The residue is taken up in acetone, filtered through 50 mg. of animal charcoal, the filtrate is evaporated and the residue recrys t-allized from methylene chloride+ether, to yield 25 mg. of 3 :20-dioxo-l 113: 18-oxido 18 hydroxy-2l-acetoxy-5apregnane melting at 167l70 C. The infrared spectrum of the compound (in a methylene chloride solution) contains bands inter alia at 2.76, 5.73, 5.83, 8.14, 9.71, 10.07 and 1020 10 mg. of this compound are stirred with 15 mg. of potassium bicarbonate, 0.3 cc. of water and 1.2 cc. of methanol for 5 hours at 20-25 C. 1 drop of glacial acetic acid is then added and the whole is diluted with 20 cc. of methylene chloride. The solution is washed with water, dried and evaporated, to yield 8 mg. of 3:20- dioxo 11B: 18 oxido 18:21 dihydr-oxy 5a pregnane as a colorless oil.

The 3 :20 bisethylenedioxy 11/3 hydroxy 21 acetoxy 5oz pregnane, used as starting material, is prepared by ketalizing 3:20 dioxo 115:21 dihydroxy 5ozpregnane with ethylene glycol and para toluenesulfonic acid, followed by acetylation with pyridine and acetic anhydride.

EXAMPLE 6 1.0 gram of 3:20 bisethylenedioxy 11p hydroxy- 21 acetoxy 5a pregnane is oxidized, as described in Example 5, with 6.0 grams of lead tetraacetate, 2.0 grams of calcium carbonate and 1.6 grams of iodine in 200 cc. of cyclohexane. The insoluble salts are filtered off and the filtrate is dried and evaporated to dryness. The residue is dissolved in 10 cc. of pyridine and the solution is added to a reaction mixture prepared from 1.0 gram of chromium trioxide, 2.0 grams of silver chromate, 10 cc. of water and 10 cc. of pyridine. The whole is heated, while being stirred, for 24 hours at 55 C., then cooled, diluted with 50 cc. of water and 80 cc. of ethyl acetate, agitated, and the undissolved salt is filtered off. The filter residue is thoroughly rinsed with ethyl acetate, and the filtrate is repeatedly agitated with water. The ethyl acetate solution is dried and then evaporated under a water-jet vacuum, to yield a yellow, oily residue (0.95 gram) which contains the 18:11 lactone of 3:20 bisethylenedioxy 115- hydroxy 21 :acetoxy 501 pregnane 18 acid. The crude product is treated, as described in Example 5, with acetic acid of 90% strength, and the resulting reaction product is isolated by preparative paper-chromatography. The pure 18: 11 lactone of 3:20 dioxo 115 hydroxy- 21 acetoxy 501 pregnane 18 acid displays in the system formamide benzene an R value of about 0.65.

12.5 mg. of the 18:11 lactone of 3:20 dioxo 115- hydroxy 21 acetoxy 511 pregnane 18 acid in 2 cc. of methanol are stirred with mg. of potassium bicarbonate and 0.3 cc. of water for 7 hours at C. The reaction mixture is then diluted with methylene chloride, washed with water, the methylene chloride extracts are dried and evaporated under a water-jet vacuum, to yield 9 mg. of the 18:11 lactone of 3:20 dioxo -115:21- dihydroxy 5 a pregnane 18 acid.

EXAMPLE 7 To a boiling suspension of 48.0 g. lead tetraacetate, 16 grams of calcium carbonate in 1.6 liters of cyclohexane are added 12.8 g. of iodine and 8.0 grams of acetoxy- 115 hydroxy 20 ethylenedioxy 511 pregnane. The mixture is boiled for another hour while being irradiated with a 500 watt lamp. The decolorized solution is cooled, filtered through Celite, the filter residue rinsed with cyclohexane, the combined filtrates washed with a thiosulfate solution of 25% strength and with water, dried and evaporated in a water-jet vacuum. There are obtained 13 grams of a crude oily product. The latter is taken up in cc. of pyridine and treated for 16 hours at 40 C. with a suspension of 8 grams of silver acetate in 40 cc. of pyridine. The cooled reaction mixture is diluted with ether and water, filtered, the aqueous layer separated, the organic phase washed with water, dried and evaporated first in a water-jet vacuum and then in a high vacuum. The residue (9.8 grams) is dissolved in benzene and chromatographed on alumina and rechromatographed on silica gel. There are obtained the following compounds:

(1) 35 acetoxy 115, 19 oxido 20 ethylenedioxyc pregnane, melting point (recrystallized from methylene chloride ether petroleum ether) 163-165 C. [o1] =+44 (c=1.15 chloroform); IR bands inter alia at 5.78 1, 8.12 1, 9.52 1, 9.65 1, 9.75 1, 9.9 1 and 10.05 1.

(2) 35 acetoxy 115,18 oxido 20 ethylenedioxy- 511 pregnane (not purified) IR bands inter alia at 5.82 1, 6.86 1, 7.36 1, 8.13 1, 9.75 1, 10.105. and 11.30 1.

(3) 35,1811 diacetoxy 115,18 oxido 20 ethylenedioxy 511 pregnane, melting point l83184 C. (recrystallized from methylenechloride/ether/petroleum ether [a] =+9 .(c=0.60 chloroform) IR bands inter alia at 5.73 1, 5.76 1, 8.12 1, 8.9 1, 9.3 1, 9.75 1, 10.1 1 and 113 1.

(4) 35 acetoxy 19 hydroxy 115,19 oxido 20- ethylene dioxy 511 pregnane melting point 167-169 C. (crystallized from methylenechloride ether petroleum ether 1] =+58 (c=0.86 chloroform) IR bands inter alia at 2.76 1, 8.80 1, 8.08 1, 9.37 1, 9.48 1 and 9.73 1.

By heating the above-mentioned compounds with acetic acid of 66% strength at 95 C. for 20 minutes there are obtained:

(1) 35 acetoxy 115,19 oxido 20 oxo 511- pregnane melting point 141142 C. recrystallized from ether/ petroleum ether [a] =+115 (c=0.74 in chloroform) 1R bands inter alia 5.80 1, 5.90 1, 8.07 1, 8.45 1, 9.72 1, 10.56 1 and 10.76 1.

(2) 35 acetoxy 115,18 oxido 20 oxo 511- pregnane melting point 144145 C. recrystallized from other [a] =+82 (c=0.74 chloroform) IR bands 5.78 1, 5.87 1, 8.08 1, 9.68 1, 9.83 1, 10.46 1, 11.25 1 and 1 1.3 8.0..

(3) 35 acetoxy-115,18 oxdo-18-hydroxy-20-oxo 511- pregnane melting at 188-189 C. (recrystallized from methylene chloride-ether-petroleum ether) [c1] =+67 (c=0.62 in chloroform) IR bands inter alia at 2.76 1, 5.80 1, 5.90 1, 8.08 1, 9.25 1, 9.38 1, 9.64 1, and 10.41 1.

(4) 35 acetoxy l15,19-0xido-19-hydroxy-20-oxo-5apregnane; IR bands inter alia at 2.75, 5.80, 5.91 8.07, 8.47, 9.20, 9.27, and 9.72.

By oxidation with 8 N solution of chromic acid in dilute sulfuric acid in acetone the two last-mentioned compounds are transformed into the corresponding lactones:

(1) The 18,11 lactone of the 35-acetoxy-115-hydroxy- 20-oxo-5o1-pregnane-18-acid melting at 187-188 C. recrystallized from methylene chloride-ether-petroleum ether [1x] =+39 (c=0.07 in chloroform); IR bands inter alia at 5.63 1, 5.78 1, 5.83 1, 8.09 1, 8.50 1, 8.68 1, 9.30 1, 9.72 1.

(2) The 11,19-lactone of the 35-acetoxy-115-hydroxy- 20-oxo-5a-pregnane-l9-acid (melting point 205-209 C.) recrystallized from methylene chloride ether; IR bands inter alia at 5.68, 5.80, 5.88, 8.08, 8.66, 8.91, 9.36 and 9.67.

What is claimed is:

1. Process for the oxidative conversion of the angular methyl groups of steroids, wherein an -hydroxysteroid unsubstituted in 18- and 19-position is treated with a lead tetraacetate having an oxidizing action in the presence of iodine.

2. Process as claimed in claim 1, wherein the reaction is carried out while irradiating the reaction mixture.

3. Process for the manufacture of 18-hydroxy-11,18- oxido-steroids wherein an l8-iodo-115-18-oxido-steroid is treated with a hydrolyzing agent.

4. Process for the manufacture of 19-hydroxy-115,19- oxido-steroids wherein a 19-iodo-115,19-oxido-steroid is treated with a hydrolyzing agent.

5. Process for the manufacture of (115 18)-lactones of 115-hydroxy-steroid-18-acids, wherein an 18-iodo-1l5, 18-oxido steroid is treated with a heavy metal chromate.

6. Process for the manufacture of (115- 19)-1actones of 1l5-hydroxy-steroid-19-acids, wherein a 19-iodo-11,19- oxido-steroid is treated with a heavy metal chromate.

7. Process for the manufacture of (115- 19)-lactones of 11fi-hydroxy-steroid-19-acids, wherein a 19-hydroxy- 115,19-oxido-steroid is treated with a member selected from the group consisting of chromium trioxide pyridine complex, chromium trioxide in acid solution and manganese dioxide.

8. Process for the manufacture of (115 19)-lactones of 115-hydroxy-steroid-l9 acids, wherein a. l9-unsubstituted 115,19-oxido-steroid is treated with a member selected from the group consisting of chromium trioxide and ruthenian tetroxide.

9. A member selected from the group consisting of a compound having the formula in which X is selected from the group consisting of hydrogen, iodine, hydroxy and 0x0, R is selected from the group consisting of hydroxy together with a hydrogen atom and 0x0, R being other than oxo when X is hydroxy, and R is selected from the group consisting of hydroxy, acetyl and hydroxy-acetyl, a carboxylic acid ester derived from a carboxylic acid having 1 to 20 carbon atoms and an ether of the hydroxy compounds and an ethyleneketal of the ketones.

10. 3a-acet0xy-20-oxo-11: 19-oxido-55-pregnane.

11. M3 :20-dioxo-1 1p: 19-oxido-1-9-hydroxy-pregnene.

12. The 9:11-lactone of A 6:20-dioxo-1'li8-hydroxypregnene-19-acid.

13. A -3-ethylenedioxy-11p: 19-oxido-20-oxo-pregnene.

14. 13 -3 :ZO-dioxo-l lfi: 19-oxido-pregnene.

15. A -3 :20 dioxo 11,8:19 oxido 19:21 diacetoxypregnene.

16. The 19:11-lactone of A -3:2t0-dioxo-l1fl-hydroxy- 2l-acetoxypregnene-l9-acid.

17. A member selected from the group consisting of a compound of the formula in which R; is selected from the group consisting of hydroxy together with a hydrogen atom and oxo, and R is selected from the group consisting of hydroxy, acetyl and hydroxy-acetyl, a carboxylic acid ester derived from a carboxylic acid having 1 to 20 carbon atoms and an ether of the hydroxy compounds and an ethyleneketal of the ketones.

18. A member selected from the group consisting of a compound of the formula in which R is a member selected from the group consisting of hydroxy together with a hydrogen atom and 0x0, R is selected from the group consisting of acetyl and hydroxyacetyl, and R is a member selected from the group consisting of two hydrogen atoms, a hydrogen atom together with a hydroxyl group and an oxo group, and carboxylic acid ester derived from a carboxylic acid having 1 to 20 carbon atoms and ethers of the hydroxy compounds and an ethylene ketal of the ketones.

19. The 8zl'l-lactone of 3:20'-dioxo-l1fl-hydroxy-5B- pregnane-18-acid.

20. The 3:20-dioxo 11,6:18 oxido 18 hydroxy-Zlacetoxy-Sa-pregnane.

21. The 3:20dioxo-11fi:l8-oxido-1 8:21-dihydroxy-5apregnane.

22. The 11,19-1actone of the 3fl-acetoxy-llfl-acetoxy- 1 1fl-hydroxy-ZO-oxo-Sa-pregnane- 19-acid.

23. A compound of the formula in which R represents a member selected from the group consisting of and O: H/ H0 24. A compound of the formula 25. A compound of the formula in which R represents a member selected from the group consisting of H and 0:

26. A compound of the formula cu -coo" i 3 u in which R represents a member selected from the group consisting of CH o and O= E E0 27. A compound of the formula and 0= 28. A compound having the formula wherein R is selected from the group consisting of hydrogen and an acyl radical of a hydrocarbon carboxylic acid having 1 to 7 carbon atoms and R is a lower alkylene radical.

29. The 10-11 lactone of 3ethylenedioxy-A -estrene- 1 1,3,17 S-diol-10/3-carboxylic acid.

References Cited UNITED STATES PATENTS Jeger et al. 260--239.55 Muller et a1 260-23955 Mystre et a1 260-23955 Mystre et a1 260239.57

LEWIS GOTTS, Primary Examiner.

J. R. BROWN, H. FRENCH, Assistant Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,385,848 May 28, 1968 Albert Wettstein et a1.

It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below: Column 12, lines 57 to 64, the formula should appear as shown below:

Column 13, lines 12 to 22, the formula should appear as shown below: a

same column 13 line 55, "8:1l-1actone" should read 18:11- lactone line 61, cancel "llB-acetoxy-".

Signed and sealed this 3rd day of February 1970.

(SEAL) Attest:

EDWARD M.FLETCHER ,'JR. WILLIAM E. SCHUYLER, JR

Attesting Officer Commissioner of Patents 

